Studies in rodents have suggested that the acetylcholine (ACh) is an essential component of the biological basis for directed attention. Questions arise, however, when one tries to model the cholinergic system as the basis for spatially and temporally precise attentional effects such as have been demonstrated in human and non-human primates. For example the smallest piece of cortical tissue which can be independently modulated by ACh may be too large to allow for the topographically precise enhancement of processing which appears to underlie attentional mechanisms. Studying cholinergic neuromodulation in a species where attention and arousal are more easily separable in behavioral tasks is essential, however such a move is hampered by a striking lack of circuit-level data regarding the structure and function of the cholinergic system in higher mammals. The proposed work will address this gap by 1) using anatomical techniques in the macaque to provide large-scale quantitative data on ACh receptor localization in cortical areas known to be involved in or modulated by attention (e.g. V4, MT and LIP), 2) using optogenetic techniques in rodents to examine the effect that naturalistic ACh release has on the processing of a visual stimulus at various stages of the visual pathway in vivo, and 3) using a high-resolution chemical sensing technique to determine the spatial and temporal profile of acetylcholine release in the visual cortex of the a) anesthetized rodent under optogenetic control and of the b) awake-behaving nonhuman primate during an attention task. PUBLIC HEALTH RELEVANCE: We will use cutting-edge technology to elucidate the function of acetylcholine in vision and visual attention. Abnormal cholinergic modulation is strongly implicated in age-related dementias including Alzheimer's disease (AD) and associated failures of vision and selective visual attention. Understanding how acetylcholine subserves normal cognitive and sensory processing will help elucidate which aspects of the deficits seen in AD are related to loss of cholinergic function and will also aid in understanding related deficits of attention, including attentional failures associated with Schizophrenia, neglect, extinction and Attention-Deficit- Hyperactivity-Disorder (ADHD).